1. Field of the Invention
The present invention relates to a novel geranyl flavonoid derivative with improved water solubility or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a method for treating cancer using the same.
2. Description of the Related Art
As the civilization advances, the incident rate of cancer grows. Accordingly, the development of an anti-cancer agent is the major issue in the field of bioscience and biotechnology. Cancer is the top-most or the second highest cause of death not only in Korea but also in other counties including USA and Japan, and death of cancer takes more than 50% of the total death rate particularly reported from the general hospitals.
Since President Nixon proclaimed war against cancer in 1971, starting with the explanation of the Novel prize winners Varmus and Bishop about the development procedure of cancer mediated by oncogene, the studies on cancer have progressed greatly for the past 40 years, during which cancer specific oncogenes or tumor suppressor genes have been identified. Even though new cancer treating drugs have been developed based on these studies on the functions and mechanisms of such genes, cancer still stays as a big mountain to conquer.
As an effort to conquer cancer, diagnostic methods have been advanced to facilitate the early diagnosis of various cancers. Progress has also been made in the treatment methods including surgical operation, ratio-therapy, chemo-therapy, and biological method, etc. The most representative cancer treatment method is the surgical operation. The surgical operation is most effective in increasing survival rate in early stage cancer patients, but is limited to some specific early stage cancers and is limited in operable regions. To overcome these disadvantages, an attempt to establish the target oriented therapy has been actively tried with targeting a cancer specific gene.
A variety of cancer cells have been targeted for chemo-therapy so far. However, a real fundamental anti-cancer drug has not been established yet, and only auxiliary drugs or the drugs only functioning to extend life for a little longer have been developed. The above treatment methods are all effective only in the early stage cancer patients or some specific cancers. So, the death of cancer still increases.
The most representative targeted cancer therapeutics being clinically used these days are Gleevec that inhibits the signal transduction, Heceptin (a breast cancer treating agent), Iressa (a lung cancer treating agent), Avastin (a colon cancer treating agent) working to inhibit angiogenesis, Suten (a kidney cancer treating agent), and Crizotinib (a lung cancer treating agent). The problem of these targeted cancer therapeutics is the resistance which is observed within 6˜12 months from the administration. To overcome the resistance, a novel drug has been continuously tried and the treatment method using combined drugs is in the center of the recent study.
To increase the treatment efficiency, studies on cancer development and metastasis, cancer cell physiology, and cancer diagnosis and treatment have been actively undergoing along with the attempts to develop not only a general anticancer agent by screening natural extracts but also a specific targeted novel agents such as an angiogenesis inhibitor and a metastasis inhibitor. Particularly, a selective anticancer agent targeting a specific molecule is on the spotlight because it is expected not only to be safer and more efficient in treatment but also to be easily applied to customized medical treatment and combination therapy.
To prevent the resistance against anticancer drugs and to inhibit the cancer recurrence, the focus of the major anticancer studies have been diverted to cancer cell metabolism, micro-environment around cancer cells, cancer stem cell generation and preservation, etc, since 2010.
STAT (Signal Transducers and Activators of Transcription) proteins act as a signaling protein in cytoplasm, which are therefore involved in signal transduction from cell membrane into nucleus and transcriptional regulation. A variety of STATs having the molecular weight of around 87˜113 kDa have been reported, which include STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6.
Among these STAT proteins, STAT3 is necessarily activated in most cancers and plays an important role in cancer development and differentiation. In many cases of malignant cancer, STAT3 activation is observed. In metastatic cancers, the continued activation of STAT3 is frequently observed. STAT3 is directly involved in tumor generation, invasion, and metastasis, and displays resistance against cancer cell apoptosis. Therefore, it is regarded as a promising anticancer strategy to screen STAT3 as a target material.
STAT proteins contain SH2 domain that is able to recognize at least one or two phosphotyrosine sequences in cytoplasm of the activated receptor. The SH2 (Src Homology-2) domain plays a role as a phosphorylation-dependent switch that regulates receptor recognition and DNA binding. As a result, STAT proteins can bridge the activation of a cell surface receptor and gene regulation (Darnell, J. E., Proc. Natl. Acad. Sci. (USA), 94:11767-11769 (1997)).
The activation of dormant STAT molecules in cytoplasm of an animal cell is achieved by the cytokine surface receptor and the growth factor receptor which is noncovalently linked to the cykine surface receptor and has Jak kinase activity or tyrosine kinase activity.
The binding between the ligand and the cell surface induces phosphorylation of tyrosine in cytoplasm of the receptor, resulting in the preparation of the STAT SH2 domain binding site. The binding with STAT on the surface of the receptor induces phosphorylation of tyrosine by Jak or receptor kinase. The phosphorylated STAT protein forms SH2 domain mediated dimer, which moves into the nucleus. In the inside of the nucleus, the dimer binds with DNA to induce transcription of a specific gene. The STAT protein signal transduction system can be stopped by dephosphorylation and protein decomposition.
Researchers have recognized the activated form of STAT in various cancers. In particular, STAT3 was identified to be activated not only in blood cancer such as leukemia but also in solid cancer such as breast cancer, head & neck cancer, melanoma, ovarian cancer, lung cancer, pancreatic cancer, and prostate cancer, suggesting that it could be an important target of anticancer study [Hua Yu and Richard Jove, Nature Review Cancer (2004), 8, 945]. Therefore, the inhibition of STAT protein leads to tumor control via combined anticancer mechanisms of apoptosis, anti-angiogenesis, and blocking immune evasion, etc. So, the inhibition of STAT protein is important as an efficient and practical technical resource for the development of an anticancer drug. And the resultant anticancer agent is expected to be more efficient in treating cancer than the conventional anticancer agents displaying linear action.
The present inventors tried to develop a novel compound exhibiting inhibitory effect on the activity of STAT3 protein. As a result, the inventors found out that the newly synthesized geranyl flavonoid derivative inhibited the expression of STAT3 target protein by inhibiting the phosphorylation of STAT3 protein so that it could bring the cancer cell growth inhibition effect in various cancer cell lines. The present inventors also confirmed that the novel geranyl flavonoid derivative inhibited the increase of the size and weight of a tumor significantly in the prostate cancer mouse model, suggesting that the novel geranyl flavonoid derivative or the pharmaceutically acceptable salts thereof and the preparation method of the same could be efficiently used for treating cancer, leading to the completion of the present invention.